title: Impairment of NO-dependent relaxation in intralobar pulmonary arteries: comparison of urban particulate matter and manufactured nanoparticles.
abstract: OBJECTIVE
  Because pulmonary circulation is the primary vascular target of inhaled particulate matter (PM), and nitric oxide is a major vasculoprotective agent, in this study we investigated the effect of various particles on the NO-cyclic guanosine monophosphate (cGMP) pathway in pulmonary arteries.
  
  
  METHODS
  We used intrapulmonary arteries and/or endothelial cells, either exposed in vitro to particles or removed from PM-instilled animals for assessment of vasomotricity, cGMP and reactive oxygen species (ROS) levels, and cytokine/chemokine release.
  
  
  RESULTS
  Endothelial NO-dependent relaxation and cGMP accumulation induced by acetylcholine (ACh) were both decreased after 24 hr exposure of rat intrapulmonary arteries to standard reference material 1648 (SRM1648; urban PM). Relaxation due to NO donors was also decreased by SRM1648, whereas responsiveness to cGMP analogue remained unaffected. Unlike SRM1648, ultrafine carbon black and ultrafine and fine titanium dioxide (TiO2) manufactured particles did not impair NO-mediated relaxation. SRM1648-induced decrease in relaxation response to ACh was prevented by dexamethasone (an anti-inflammatory agent) but not by antioxidants. Accordingly, SRM1648 increased the release of proinflammatory mediators (tumor necrosis factor-alpha, interleukin-8) from intrapulmonary arteries or pulmonary artery endothelial cells, but did not elevate ROS levels within intrapulmonary arteries. Decreased relaxation in response to ACh was also evidenced in intrapulmonary arteries removed from rats intratracheally instilled with SRM1648, but not with fine TiO2.
  
  
  CONCLUSIONS
  In contrast to manufactured particles (including nanoparticles), urban PM impairs NO but not cGMP responsiveness in intrapulmonary arteries. We attribute this effect to oxidative-stress-independent inflammatory response, resulting in decreased guanylyl cyclase activation by NO. Such impairment of the NO pathway may contribute to urban-PM-induced cardiovascular dysfunction.
authors.affiliation: Université Bordeaux 2, Bordeaux, France. arnaud. courtoise@tox.u-bordeaux2.fr
authors.forename: Arnaud
authors.initials: A
authors.lastname: Courtois
authors.forename: Pascal
authors.initials: P
authors.lastname: Andujar
authors.forename: Yannick
authors.initials: Y
authors.lastname: Ladeiro
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baudrimont
authors.forename: Estelle
authors.initials: E
authors.lastname: Delannoy
authors.forename: Véronique
authors.initials: V
authors.lastname: Leblais
authors.forename: Hugues
authors.initials: H
authors.lastname: Begueret
authors.forename: Marie Annick Billon
authors.initials: MA
authors.lastname: Galland
authors.forename: Patrick
authors.initials: P
authors.lastname: Brochard
authors.forename: Francelyne
authors.initials: F
authors.lastname: Marano
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.forename: Bernard
authors.initials: B
authors.lastname: Muller
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002417:Cattle; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D053758:Nanoparticles; D009569:Nitric Oxide / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000393:Air Pollutants; D009569:Nitric Oxide